In the quarter of a century since the pioneer demonstration that an enzymic deficiency can be the cause of a known disease - namely the lack of the specific glucose-6-phosphatase in von Gierke's disease - more than 300 cases of glycogen storage disease (GSD) have been studied and classified in our laboratory in St. Louis. Most of the glycogen storage diseases appear to follow an autosomal recessive pattern of inheritance just as do many other heritable metabolic diseases. Our studies utilizing tissues from these human GSD mutants have complimented an on-going effort to purify the enzymes involved in glycogen synthesis and degradation, and to study the properties and mechanisms of action of the purified proteins. The present proposal is aimed at attempting to resolve a few of the unanswered questions in glycogen metabolism. The problems to be addressed include (a) the biochemical difference(s) between "infantile" and "adult" forms of lysosomal alpha-glucosidase deficiency (Type II GSD), (b) the mechanism by which the branch points are introduced into the polysaccharide present in tissues of the Type IV GSD patient who lacks the glycogen branching enzyme, (c) the control of the level of glycogen attainable and characteristic of different tissues, and (d) a better understanding of the enzymatic reactions by which glycogen is synthesized and degraded. Fibroblasts derived from patients with various types of glycogen storage disease, with metabolic acidosis and from normal individuals will be cultured and studied. A principal additional objective is to obtain more follow-up records of previously studied patients and to utilize them to record as completely as possible the incidence, common complications experienced and prognosis for the entire group of glycogen storage diseases.